The present invention relates to pro-inflammatory and anti-inflammatory proteins.
Brain injury such as trauma, ischemia or autoimmune-inflammation leads to an inflammatory tissue response involving both activated, resident and infiltrating cells. In brain ischemia this inflammatory reaction is characterized by an early influx of polymorphonuclear leukocytes, primarily neutrophils, into the zone of injury followed by a late infiltration of activated microglia and blood monocyte/macrophages (Dereski et al. (1992) Neurosci. Res. Commun. 11:179-186; Ramsay et al. (1992) Lancet 339:1054-1055). Infiltrating leukocytes as well as activated resident glial cells may exert a cytotoxic effector function by releasing reactive oxygen species, nitric oxide, proteinases, inflammatory cytokines or excitotoxins such as glutamate or quinolinic acid and, therefore, have been implicated in the pathogenesis of cerebral ischemia and stroke. (Kochanik and Hallenbeck (1992) Stroke 23:1367-1379; Lees (1993) J. Neurol. Sci. 114:119-122; Wood (1995) Neurol. Res. 17:242:248). The specific mechanisms responsible for the initiation and propagation of the inflammatory reaction in response to focal and transient brain ischemia are not fully elucidated. Studies showing a very early and sustained upregulation of the pro-inflammatory cytokines TNF alpha and IL-1 in the ischemic area and a more delayed increase for mediators such as IL-6, MCP-1 or MIP-1 alpha provide evidence for a specific role of brain cytokines in this process (Buttini et al. (1994) Mol. Brain Res. 23:126-134; Kim et al. (1995) J. Neuroimmunol. 56:127-134; Wang et al. (1995) Stroke 26: 661-666; Buttini et al. (1996) Neurosci. 71:1-16; Yoshimoto et al. (1997) Acta Neuropathol. 93:154-158).
The molecular mechanism of inflammatory cell infiltration involves a complex series of adhesive interactions between circulating leukocytes and vascular endothelium adjacent to the inflammatory site mediated by locally produced pro-inflammatory cytokines and chemoattractants (Butcher (1991) Cell 67:1033-1036; Carlos and Harlan (1994) Blood 84:2068-2101). Among the chemoattractants, chemokines are a family of small cytokines thought to mediate the directional migration of specific target populations of leukocytes along concentration gradients through the endothelial cell layer to the site of lesion (Baggiolini et al. (1994) Adv. Immunol. 55: 97-179). This cascade of events, however can display a high degree of specificity in relation to the inflammatory stimulus, the stage of the inflammatory response and the tissue or organ involved (Butcher et al., loc. cit.).
The family of chemokines can be subdivided in two main groups based on the position of the first two of four conserved cysteine residues which are separated by a single amino acid residue in the CXC family of chemokines or juxtaposed in the CC family (Baggiolini et al., loc. cit.; Strieter et al. (1996) J. Immunol. pp. 3583-3586). In general, CXC chemokines are potent chemoattractants for neutrophils whereas CC chemokines act on monocytes but also on basophils, eosinophils and T-lymphocytes. Recently several novel CC chemokines have been discovered by homology searches in EST databases (Rossi et al., (1997) J. Immunol., 158: 1033-1036; Hieshima et al. (1997) J. Biol. Chem., 272:5846-5853). The biological role of these proteins as well as their physiological functions remains to be determined.
The present invention is based on the discovery of novel polypeptides, referred to herein as the xe2x80x9cST38.2xe2x80x9d polypeptides, which function as chemokines related to inflammatory and immune responses, particularly related to neuroinflammatory responses.
In accordance with the present invention ST38.2 polypeptides are encoded by nucleic acid molecules comprising nucleic acid molecules selected from
(a) a nucleic acid molecule or a complement of a nucleic acid molecule set forth in SEQ ID NO:1;
b) a nucleic acid molecule or a complement of a nucleic acid molecule encoding a polypeptide set forth in SEQ ID NO:2 or SEQ ID NO:3;
(c) a nucleic acid molecule capable of hybridizing to a nucleic acid molecule of (a) or (b); and
(d) a nucleic acid encoding variations, homologues, derivatives or fragments of the polypeptides defined by (a), (b) or (c).
Some ST38.2 polypeptides possess the pro-inflammatory activities of inducing migration of leukocytes and/or activating leukocytes in a dose-dependent manner. These polypeptides are useful for increasing cell layer permeability to allow drugs to circulate to their respective targets, which is desirable in treating tumors and infectious diseases. These peptides are important mediators in host defense, and can be used as part of wound healing therapy. Polypeptides which activate leukocytes are also useful for treating tumors since activated leukocytes can kill or inhibit tumors. Other ST38.2 polypeptides are agonists of chemotaxis and/or leukocyte activation, possess anti-inflammatory activity and are useful in the treatment of inflammatory or immune diseases.